This revision of a competitive renewal seeks to continue our innovative and highly productive research program which has the goal of understanding the etiology, consequences and causes of desistance of drug use disorders (DUD) utilizing data available on the entire population of Sweden of unparalleled completeness and depth. We have eight specific aims which focus on the etiology and course and consequences of DUD. These aims are: i) to develop a structural equation (SEM) based approach to co-relative analyses and then apply it to critical risk factors for DUD available in Sweden, permitting a more rigorous assessment than hitherto possible of the degree to which risk factor-DUD associations are due to familial confounding versus causal effects; ii) to examine how strongly DUD is predicted by measures of IQ and personality at age 18 available on ~ 97% of all Swedish males born 1951-1975 and to clarify the degree to which these associations are likely causal; iii) to explore the similarity and differences in risk factors for UD and smoking in over 1.2 million fertile women for whom smoking status is available as part of nurse-midwife's reports; iv) to explore how factors related to immigration, with a focus on macro-level contextual characteristics (i.e., residential segregation), impact risk for DUD among first and second generation immigrants to Sweden using analytical Geographic Information Systems (GIS) methods; v) to clarify how risk factors for DUD vary by gender using discordant opposite-sex relative pairs and the degree to which these risk factors are specific to DUD versus shared with other key externalizing syndromes of alcohol use disorders and crime; vi) to develop a comprehensive SEM for DUD in adoptees, twins, siblings, half-siblings, and typical, not-lived-with and step- parents that will permit joint estimation of four sources of familial-environmental effects, to examine developmental dynamics in the genetic and environmental risk factors for DUD from adolescence to middle age utilizing a longitudinal twin-sibling design and to clarify key mediating mechanisms from distal to more proximal risk factors by constructing a phenotypic-developmental SEM model for DUD that incorporates a wide array of genetic and environmental risk factors; vii) to develop longitudinal models to clarify the social, psychiatric and medical consequences of DUD using co-relative designs to control for familial confounding and viii) to explore the predictors of desistance from DUD on both the latent and specified risk factor level and clarify the causal nature of these associations via co-relative designs. We will use comprehensive data from multiple nationwide data sources in Sweden on 11.8 million men and women to accomplish these goals. Applying the deep expertise of our research groups at Virginia Commonwealth and Lund University in drug abuse research, social and genetic epidemiology and causal modeling to a uniquely powerful sample, we expect this study to have important implications for DUD research, prevention and policy.